This invention relates to aqueous dispersions of perfluoro compounds useful as gas transfer agents and for drug delivery and other therapeutic applications in animals including man. Typical perfluoro compounds, dispersions and uses are described in U.S. Pat. Nos. 3,911,138 to Clark and 4,105,798 to Moore and Clark. The perfluoro compounds described in these patents are essentially non-toxic and therefore eminently suitable for therapeutic uses.
Aqueous dispersions of perfluoro compounds, such as those of the U.S. patents cited above, are prepared by dissolving a surfactant in water, adding the perfluoro compound, and then agitating the mixture until a uniform dispersion of the perfluoro compound is obtained. Since the perfluoro compounds are extremely hydrophobic, considerable mechanical energy is required for effective dispersion, such as high pressure homogenization or sonically induced cavitation. Depending on selection of perfluoro compound, surfactant and proportions of ingredients, highly stable dispersions of very small average particle size, on the order of about 0.1 to 1.0 micron in diameter, are obtained. In such cases, the dispersions are essentially transparent and are sometimes described in the literature as "microemulsions" (U.S. Pat. No. 3,778,381 to Rosano et al). However, in other cases useful dispersions can be prepared having larger average particle sizes and these may be borderline between suspensions and emulsions. Accordingly, the term "dispersion" is used in this specification to indicate, generically, any two-phase system, whether a suspension, emulsion or microemulsion, and whether oil-in-water, water-in-oil or invert, and the term "perfluoro compound phase" means the perfluoro compound-containing particles of the dispersion. For purposes of illustration, the emphasis in this specification will be on the more preferred compositions, viz., emulsions or microemulsions of the oil-in-water type.
To overcome the difficulty of forming good dispersions with the extremely hydrophobic perfluoro compounds it is common practice to prepare the dispersions using a high proportion of surfactant to perfluoro compound (of the order of about 1:5 by weight) and low concentrations of perfluoro compound (about 20-25% w/v). This facilitates not only good dispersability but also small particle size. The resulting dispersions have good stability and low viscosity which promote their rapid transit throughout the cardiovascular system, particularly in capillaries or vessels which are blocked or constricted. Such dispersions will also exhibit reduced retention in the reticuloendothelial system (RES). However, the goal of optimizing the dispersion process and physical qualities of the dispersion (particularly stability and viscosity) imposes a practical upper limit on the amount of perfluoro compound in the finished dispersions and thereby also limits the gas transfer capacity of the dispersions and their capacity for treatment of hypoxic cells and for carrying lipophilic drugs in the manner described in copending, commonly assigned U.S. application Ser. No. 580,760 filed Feb. 17, 1984. The subject matter of said application and its predecessor applications is incorporated herein by reference.
Additionally, while it is possible (although not always practical because of formulation difficulties) to select surfactants and/or dosages thereof which are sufficiently non-toxic by LD.sub.50 standards, other toxic responses attributable to the surfactants, such as complement activation, have been reported. This has led either to excluding the surfactants from use in perfluoro compound dispersions or to reduction in their concentration with proportionate reduction in the amount of perfluoro compound which can be effectively dispersed.
In summary, it has heretofore been considered necessary, in order to satisfy the requirements of efficient dispersability, low particle size, stability and viscosity on the one hand, and sufficient gas transfer capacity and biological compatibility on the other, to maintain fairly low concentrations of perfluoro compound in aqueous dispersions thereof, on the order of no more than about 25% (w/v), i.e., about 25 g/100 ml. of the total dispersion, so that the amount of surfactant may also be kept low, on the order of no more than about 2.gtoreq.5% (w/v), i.e., about 2-5 g/100 ml. of the total dispersion.